The identification of human mammary progenitor cells and understanding their regulation is critical to enumerating the origins and events that control pathologic conditions. Determining the identity and activity of normal primitive cells could lead t a better understanding to the connection between stem cell biology and cancer. Our study is directed towards understanding the mechanisms that underlie human breast development and the regulation of primitive progenitor cells by hormone-growth factor signaling. The limited understanding of human breast development and stem cell biology has largely been due to the lack of appropriate model systems and assays to detect, analyze, and characterize stem cell properties. In recent years, our laboratory has developed and optimized various in vivo and in vitro tools to study the biology and mechanisms governing human breast development We have pioneered and implemented the use of an innovative in vivo model to study human mammary development by exploiting the mouse mammary fat pad of immunocompromised mice as a source of important endocrine signaling events and using grafted human stroma to support the growth and differentiation of the human mammary epithelium. In recent work, we have identified i) four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) within human breast tissues that differ on the basis of CD24, EpCAM and CD49f expression, ii) the existence of bipotent progenitors that contribute to structurally distinct elements (ducts and lobule/alveoli), iii) the hormonal combinations that enhance stem/progenitor cell activity within human epithelial cells, and iv) a hormone growth factor mechanism through TBX3 expression can regulate breast stem-like cells.
In Aim 1 of this project, we will delineate the epithelial hierarchy in adult human breast tissue.
In Aim 2, we will determine how hormone-growth factor signaling regulates human breast progenitor cell activity. Our studies provide innovative insight into the identity of human breast progenitor cells and provide critical molecula underpinnings by which hormones drive human breast progenitor cell morphogenesis that could serve as focal points during the development of pathological conditions.

Public Health Relevance

The identity of primitive cells within human breast tissues is largely unknown as well as the precise hormonal factors and signaling pathways that regulate their proliferation, lineage commitment, and differentiation. Our broad goal is to study and characterize normal adult human mammary stem/progenitor cells and understand the hormonal/growth factor mechanisms that underlie their regulation. These studies are essential for understanding mammary progenitor cell dysregulation in diverse types of human pathological conditions including the formation of breast cancer.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD073035-01
Application #
8337917
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Raiten, Daniel J
Project Start
2012-07-25
Project End
2017-05-31
Budget Start
2012-07-25
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$522,384
Indirect Cost
$200,182
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Arendt, Lisa M; St Laurent, Jessica; Wronski, Ania et al. (2014) Human breast progenitor cell numbers are regulated by WNT and TBX3. PLoS One 9:e111442
Skibinski, Adam; Breindel, Jerrica L; Prat, Aleix et al. (2014) The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment. Cell Rep 6:1059-72
Kottakis, Filippos; Foltopoulou, Parthena; Sanidas, Ioannis et al. (2014) NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells. Cancer Res 74:3935-46
Phillips, Sarah; Prat, Aleix; Sedic, Maja et al. (2014) Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation. Stem Cell Reports 2:633-47
Arendt, Lisa M; McCready, Jessica; Keller, Patricia J et al. (2013) Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 73:6080-93